Parkinson's disease is characterized by motor and cognitive impairments and cell death in a part of the brain called the substantia nigra pars compacta (SNc). Parkinson's patients also get aggregations of 1-synuclein in the brain, which may be toxic to brain cells. Our long-term goal is to understand better the early biological events in Parkinson's disease and how they relate to the cognitive and motor symptoms of the disease. The objective of this particular application is to get a preliminary understanding of the role that gangliosides play in the cognitive impairments and neuropathology associated with Parkinson's disease. Gangliosides are lipids expressed in every tissue in the body. They are particularly abundant in the brain, but their brain distribution is abnormal in Parkinson's disease. The general hypothesis of the proposed research is that a partial reduction of the more complex gangliosides may prevent cell death, reduce 1-synuclein aggregation, and alleviate cognitive and motor deficits in three mouse lines that model various characteristics of Parkinson's disease. Because the types of cognitive impairments exhibited by Parkinson's patients have not been investigated in mice, mice will first be trained on complex behavioral tasks designed to measure "executive" functions. Executive functions are basic cognitive processes that are necessary for engaging in higher-order cognitive processes, such as attention, extradimensional shift, impulse control, and short-term working memory. The models include mice injected with the neurotoxin MPTP, a transgenic expressing mutant 1- synuclein, and a knockout mouse lacking PARK2. Once baseline behavioral and motor performance is established, mice will receive an injection of a small-interfering RNA (siRNA) construct targeting GD3 synthase (GD3S), or a scrambled control. GD3S is responsible for synthesis of two of the four major brain gangliosides, and elimination of this enzyme in a mouse model of Alzheimer's disease restores good cognitive function, blocks cell death and oxidative stress, and nearly eliminates amyloid plaque formation. The GD3S-siRNA construct will be propagated by a recombinant adeno-associated viral vector (rAAV), and injected into the dorsal third ventricle of the brain to promote dispersion. Following the surgery, additional motor and behavioral tests will be conducted, followed by processing of the brains for neurochemistry and immunohistochemistry. Successfully reducing 1-synuclein aggregation, cell death, and cognitive impairments in the mouse models may provide insight into new treatment strategies for Parkinson's disease-treatments that could restore function or slow the disease process Parkinson's patients. PUBLIC HEALTH RELEVANCE: Current treatments for Parkinson's disease focus on dopamine replacement to improve motor function, but do nothing to improve the cognitive impairments common among Parkinson's patients. The research proposed herein is a novel treatment approach-inhibition of GD3 synthase. The effects of GD3S inhibition are to reduce aggregates of proteins such as 1-synuclein, reduce oxidative stress, prevent neurodegeneration, and improve motor and cognitive function.